The basic objective of this program project continues to be the study of the mechanism of age-related changes in the adrenergic pharmacology of the cardiovascular and central nervous systems. While there is a rich literature on differences between drug response in young and aged organisms, little is known about the mechanisms which underlie these differences. In this program, we will study age-related changes in drug responsiveness in both man and in experimental animal models. The molecular mechanisms for such changes, in terms of receptors, of adenylate cyclase, of phosphoinositol turnover, and of the regulation of presynaptic function will be pursued biochemically using both human and animal tissues. Physiological correlates will be examined using techniques of electrical recording, in vivo chronoamperometry, and stimulation. Morphological correlates in both neuronal and non-neuronal elements will be evaluated. Tissue transplantation will be utilized to determine the intrinsic versus extrinsic nature of any age-related central nervous changes. The major hypothesis to be pursued is that pre- and/or postsynaptic changes in peripheral autonomic neuroeffector mechanisms or in CNS synaptic circuitry will underlie many of the alterations in drug responsitivity seen with aging.